MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

Nat Commun. 2014 Jun 9:5:3970. doi: 10.1038/ncomms4970.

Abstract

Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin ß4 (Tß4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or Tß4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the Tß4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as Tß4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing Tß4 (Tß4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Blood Vessels / growth & development*
  • Blood Vessels / metabolism
  • Connective Tissue Growth Factor / metabolism*
  • Cysteine-Rich Protein 61 / metabolism*
  • Hibernation
  • Hindlimb / blood supply
  • Ischemia / metabolism
  • Ischemia / physiopathology
  • Mice
  • Myocardial Contraction
  • Rabbits
  • Swine
  • Trans-Activators / physiology*

Substances

  • CCN1 protein, mouse
  • CCN2 protein, mouse
  • Cysteine-Rich Protein 61
  • Mrtfa protein, mouse
  • Trans-Activators
  • Connective Tissue Growth Factor